Influenza A viruses (IAV) are significant human pathogens causing yearly epidemics and occasional pandemics. Past pandemics have resulted in significant morbidity and mortality. The 1918 influenza pandemic was thought to have resulted in the death of at least 675,000 people in the U.S., and 40 million people worldwide. Pandemics in 1957 and 1968, while less severe, were also of major public health importance. A novel influenza A virus of swine origin became pandemic in 2009, causing the first pandemic in 41 years. The virus has spread efficiently to both the Northern and the Southern Hemispheres and has been associated with over 16,000 deaths. Zoonotic infections with H1N1 influenza viruses that evolved initially from the 1918 virus and adapted to swine threatened a pandemic in 1976 (1976 swH1N1) and a novel reassortant H1N1 virus caused a pandemic in 2009-2010 (2009 pH1N1). We previously showed that protection from severe 2009 pH1N1 infection is conferred by vaccination or prior infection with 1976 swH1N1 or 1918 in mice supporting available epidemiological data. In a follow-up experiment, we sought to demonstrate cross-protection by immunization with 2009 pH1N1 or 1976 swH1N1 vaccines following a lethal challenge with the 1918 influenza virus. Mice were immunized with 1976 swH1N1, 2009 pH1N1, 2009 seasonal trivalent, or 1918 virus vaccines and challenged with a lethal dose of the 1918 influenza virus. Cross-reactive antibody responses were assessed and protection monitored by survival, weight loss, and pathology. Vaccination with the 1976 swH1N1 or 2009 pH1N1 vaccines protected mice from a lethal challenge with 1918, and these mice lost no weight and had significantly reduced viral load and pathology in the lungs. Protection was likely due to cross-reactive antibodies detected by microneutralization assay. Our data suggest that the general population may have some protection from a future 1918-like pandemic because of prior infection or immunization with 1976 swH1N1 or 2009 pH1N1. Obesity was identified as an independent risk factor for severe or fatal infection with 2009 pandemic H1N1 influenza (2009 pH1N1), but was not previously recognized for previous pandemic or seasonal influenza infections. A study was conducted to evaluate the role of obesity as an independent risk factor for severity of infection with 2009 pH1N1, seasonal H1N1, or a pathogenic H1N1 influenza virus in a mouse model. Diet-induced obese (DIO) mice and their non-obese, age-matched control counterparts were inoculated with a 2009 pH1N1, A/California/04/2009 (CA/09) virus, a current seasonal H1N1 virus, A/NY/312/2001 (NY312), or a pathogenic 1918-like H1N1 virus, A/Iowa/Swine/1931 (Sw31). Following inoculation with CA/09, DIO mice had higher mortality (80%) than control mice (0%) and lost more weight during infection. No effect of obesity on morbidity and mortality was observed during NY312 or Sw31 infection. Influenza antigen distribution in the alveolar regions of the lungs was more pronounced in DIO than control mice during CA/09 infection at 3 days post-inoculation (dpi), despite similar virus titers. During CA/09 infection, localized interferon-&#946;and proinflammatory cytokine protein responses in the lungs were significantly lower in DIO than control mice. Conversely, serum cytokine concentrations were elevated in DIO, but not control mice following infection with CA/09. The effect of obesity on differential immune responses was abrogated during NY312 or Sw31 infection. Together, these data support epidemiological reports that obesity may be a risk factor for severe 2009 pandemic H1N1 influenza infection, but the role of obesity in seasonal or highly virulent pandemic influenza infection remains unclear. In a collaboration with Heinz Feldmann, NIAID Laboratory of Virology, the pathogenicity of 2009 pandemic H1N1 viruses was studied in a nonhuman primate model using cynomolgus macaques. In this experimental pathogenesis study, the parameters of clinical disease, virology, host immune response, and histopathology were compared among animals infected with different strains of the 2009 pandemic H1N1 virus along with a current seasonal H1N1 virus. Infections with the pandemic isolates resulted in more severe disease than infections with seasonal influenza, however heterogeneity in disease progression was noted between pandemic strains used. The clinical course and disease progression in nonhuman primates mimicked influenza infection in humans, supporting the use of this experimental model for influenza.